Use of camptothecin derivatives, with reduced gastrointestinal toxicity

ABSTRACT

Use of sodium chloride for preparing an agent intended to reduce or eliminate the gastrointestinal side effects induced by the administration of camptothecin derivatives, characterized in that the sodium chloride solution is administered orally.

This application is a 371 of PCT/FR99/01916 filed Aug. 3, 1999 whichclaims benefit of Ser. No. 60/096,318 filed Aug. 12, 1998.

The present invention relates to the use of camptothecin derivatives,without entailing any gastrointestinal intolerance side effects, or withreduced gastrointestinal side effects. The present invention alsorelates to the use of sodium chloride solutions to reduce thegastrointestinal side effects entailed by the administration ofcamptothecin derivatives.

It is known that the administration of camptothecin derivatives causesmany side effects. In particular in the gastrointestinal tract, theymost commonly cause very serious vomiting and diarrhoea which can leadto interruption of the treatment.

European patent EP 137145 describes camptothecin derivatives of generalformula:

in which, in particular, R₁ is hydrogen, halogen or alkyl, X is achlorine atom or NR₂R₃ in which R₂ and R₃, which may be identical ordifferent, can represent a hydrogen atom, an optionally substitutedalkyl radical, a carbocycle or a heterocycle which are optionallysubstituted, or alkyl radicals (optionally substituted) forming, withthe nitrogen atom to which they are attached, a heterocycle optionallycontaining another hetero atom chosen from O, S and/or NR₄, R₄ being ahydrogen atom or an alkyl radical, and in which the X—CO—O— group islocated in positions 9, 10 or 11 on ring A. These camptothecinderivatives are anticancer agents which inhibit topoisomerase I, amongwhich irinotecan, for which X—CO—O— is[4-(1-piperidino)-1-piperidino]carbonyloxy, is an active principle whichis particularly effective on solid tumours and especially colorectalcancer.

Patent application EP 74256 also describes other camptothecinderivatives which are also mentioned as anticancer agents, in particularderivatives which have a structure similar to the structure given aboveand in which X—CO—O— is replaced with a radical —X′R′ for which X′ is Oor S, and R′ is a hydrogen atom or an alkyl or acyl radical. Othercamptothecin derivatives have also been described, for example, inpatents or patent applications P 56692, EP 88642, EP 296612, EP 321122,EP 325247, EP 540099, EP 737686, WO 9003169, WO 9637496, WO 9638146, WO9638449, WO 9700876, U.S. Pat. No. 7104894, JP 57 116015, JP 57 116074,JP 59 005188, JP 60 019790, JP 01 249777, JP 01246287, JP 91/12070, orin Canc. Res., 38 (1997) Abst. 1526 or 95 (San Diego—12-16 April), Canc.Res., 55(3), 603-609 (1995) or AFMC Int. Med. Chem. Symp. (1997) Abst.PE-55 (Seoul—27 July-1 August).

Camptothecin derivatives are conventionally administered by injection,more particularly intravenously in the form of a sterile solution or ofan emulsion. Camptothecin derivatives can also be administered orally,in the form of solid or liquid compositions.

Camptothecin derivatives can also be administered in combination withother anticancer agents, such as for example cisplatin, oxaliplatin,Tomudexo®(N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-theonyl-L-glutamicacid)), Taxotere® (docetaxel), 5-fluorouracyl and thymidilate synthaseinhibitors.

Unfortunately, among the clinical side effects linked to treatment withcamptothecin derivatives, the onset of diarrhoea (of grade 3 or 4), ofcholinergic syndrome, of nausea or vomiting is especially noted. Inparticular, in 38% of patients, severe diarrhoea is observed, which canendanger the life of the patients as a result of dehydration and/orassociated infection.

Many strategies have been implemented in order to combat intestinaltoxicity due to the administration of the active principle and to reduceit, but these have proved unsuccessful hitherto. The result of this isthat camptothecin derivatives can only be used by very experiencedoncologists and only for certain categories of patients who can toleratethem.

It has now been found, and it is this which forms the subject of thepresent invention, that protection against the gastrointestinal lesionsinduced by treatment with camptothecin derivatives can be obtained bythe administration of a sodium chloride solution. The protection resultsin the reduction or even the specific elimination of thegastrointestinal side effects, without the systemic exposure to theactive principle or the antitumour activity being reduced.

The present invention relates to the use of sodium chloride forpreparing an agent intended to reduce or eliminate the gastrointestinalside effects induced by the administration of camptothecin derivatives.According to the invention, the agent intended to reduce or eliminatethe gastrointestinal side effects induced by the administration ofcamptothecin derivatives is an aqueous sodium chloride solution.

The protection is obtained by administration of a sodium chloridesolution simultaneously with the administration of the camptothecinderivative, or alternatively several days before and then simultaneouslywith the administration of the camptothecin derivative.

This surprising effect has an entirely favourable consequence and, inparticular, makes it possible to avoid treatment interruptions linked tothe excessively severe gastrointestinal side effects.

According to the invention, the sodium chloride solution used is anaqueous solution which has a concentration of between 4 and 13 g/l. Itis administered orally.

Preferably, the sodium chloride solution is used at the concentration of9 g/l.

The sodium chloride solution is prepared according to conventionalmethods by dissolving sodium chloride in water (purified water, sterilewater, for example). It can also comprise other agents, such as inparticular sweeteners or flavourings.

The sodium chloride solution can be administered in a proportion of 5 to10 ml/kg/administration, once or twice a day, from 5 days before thestart of treatment to 1 day after stopping treatment, for a duration oftreatment with the camptothecin derivative of between 1 and 5consecutive days. According to another method of administration, thesodium chloride solution is administered in a proportion of 5 to 10ml/kg/administration, once or twice a day, for the duration of thetreatment, preferably in a proportion of 10 ml/kg/administration, twicea day, for a duration of treatment with the camptothecin derivative ofbetween 1 and 14 consecutive days. Preferably, the sodium chloridesolution is used according to this second method of administration.

The camptothecin derivative is administered by injection, preferablyintravenous injection, or orally.

When the camptothecin derivative is administered intravenously, thesecompositions can also contain adjuvants, in particular wetting,isotonicity, emulsifying, dispersing and stabilizing agents. Irinotecan(CPT-11) is in particular administered in solution in a medium forintravenous injection, at doses of between 175 to 500 mg/m².

The camptothecin derivatives can also be administered orally, in theform of solid compositions such as, for example, hard capsules made ofgelatin or of a semi-solid hydrophilic matrix. They can also beadministered in the form of tablets, pills, hard capsules, softcapsules, powders or granules. Preferably, the oral compositions can betablets. In all these compositions, the active product is mixed inparticular with one or more inert diluents or adjuvants, such as sugars,sugar derivatives or hydrophilic macromolecules, in particular sucrose,lactose, glucose, maltose, D-fructose, sorbitol, starches such as wheatstarch, corn starch or rice starch, cellulose and its derivatives suchas ethylcellulose, methylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, methylhydroxymezhylcellulose,methylhydroxypropylcellulose, or carboxymethylcellulose, for example, orgums such as gum arabic, gum tragacanth, guar gum, alginates,carrageenates or dextrin, for example, or proteins, synthetic productssuch as polyvinylpyrrolidone, high molecular weight PEGs, oralternatively such as inorganic products, for instance colloidal silicasor silicates. These compositions can comprise other substances, such asfor example lubricants such as magnesium stearate or a coating intendedfor controlled release. They can also be administered in the form ofpharmaceutically acceptable solutions, suspensions, emulsions, syrupsand elixirs containing inert diluents such as water or oils such asliquid paraffin. These compositions can also comprise substances otherthan diluents, such as wetting, sweetening or flavouring products suchas, in particular, sugars or polyols.

It is understood that the presentation kits for the formulation ofcamptothecin derivatives and of an agent based on sodium chloride, whichis intended to reduce or eliminate the gastrointestinal side effectsinduced by the administration of camptothecin derivatives, also fallwithin the context of the present invention.

Any form of presentation kits can be suitable, in particular, by way ofexample, presentations in twin-bottle or multiple-bottle form,presentations in the form of a bottle containing the camptothecinderivative and of one or more vial(s) containing the agent,presentations in the form of an infusion bag containing the camptothecinderivative and of one or more bottle(s) or vial(s) containing the agent,presentations which involve an oral presentation comprising thecamptothecin derivative and one or more bottles or vials comprising theagent. It is understood that in the above bottles or vials, the sodiumchloride can be in the form of powder to be diluted, or in the form of asolution, in particular a ready-to-use solution.

Experimental Studies:

The present invention has been demonstrated in various studies carriedout in mice and dogs, under the conditions described below.

Preparation of an Injectable Solution:

A solution for injection based on irinotecan hydrochloride trihydrate isprepared in a proportion of 20 mg/ml, in the presence of the followingconstituents:

irinotecan hydrochloride trihydrate . . . 20 mg

D-sorbitol . . . 45 mg

lactic acid . . . 0.9 mg

sodium chloride . . . qs pH=3.5

water for injectable preparations . . . qs 1 ml

1/Experimental Studies in Mice

1.1/Study I

Evaluation of the protective effect of an orally administered sodiumchloride solution on the intestinal toxicity of intravenouslyadministered CPT-11.

CD1 male mice (5 to 6 weeks old) separated into two groups of 10receive, in each of the 2 groups, an intravenous injection (20 ml/kg ata rate of 0.5 ml/minute) of an aqueous solution of CPT-11 in sodiumchloride at 9 g/l, at the dose of 40 mg/kg (approximately 120 mg/m² ofbody surface), for 5 consecutive days from day 6 to day 10. This periodof treatment is followed by a period of 3 days without treatment (up today 13). In one of the groups, the mice also receive, orally, an aqueoussodium chloride solution at 9 g/l at a volume of 20 ml/kg/day (i.e. 10ml/kg/administration, twice a day approximately 10 hours apart) for 10consecutive days (days 1 to 10) (CPT-11/NaCl group). The animals in thesecond group do not receive 9 g/l sodium chloride orally (CPT-11 group).

The mortality and the clinical symptoms are observed every day. The bodyweight is recorded on days 1, 6, 11 and 13. The mice are sacrificed andautopsied on day 13. The complete gastrointestinal tract is removed fromall of the mice. The gastrointestinal tract of the mice which survivedto the end of the observation period is subjected to examination under amicroscope.

The mortality linked to the administration of CPT-11 observed on days 6and 7 is observed in 7/15 mice in the CPT-11 group and in only 2/10 micein the CPT-11/NaCl group. Reductions in motor activity, trembling,convulsions and/or respiratory difficulties linked to the administrationof CPT-11 are occasionally observed after the administration of CPT-11.Loss of body weight is observed in the CPT-11 and CPT-11/NaCl groupsthroughout the treatment with CPT-11. The loss of body weight is greaterin the CPT-11 group than in the CPT-11/NaCl group and persists after theend of the treatment in the CPT-11 group.

The nature of the microscopic lesions observed in the intestinecorresponds to those expected with an anticancer agent. The lesions aremainly in the small intestine for the two groups. These lesions, whichare moderate to pronounced overall, are characterized by a loss ofcrypts and shortening of the villi. The intestinal lesions are lesssevere in the CPT-11/NaCl group, in particular, minimal losses thiscrypts are observed only occasionally.

In conclusion, the oral administration of an isotonic sodium chloridesolution (9 g/l) at 10 ml/kg/administration twice a day (20 ml/kg/day)for 5 days before, and during, the intravenous administration of CPT-11for 5 days prevents the occurrence of the intestinal histopathologicallesions induced by CPT-11.

1.2/Study II

Evaluation of the protective effect of various protocols of oraladministration of a sodium chloride solution on the intestinal toxicityof CPT-11.

CD1 male mice (5 or 6 weeks old) are divided into 5 groups of 10 animalsand receive an intravenous injection (20 ml/kg at a rate of 0.5ml/minute) of an aqueous solution of CPT-11 in sodium chloride at 9 g/l,at the dose of 40 mg/kg (approximately 120 mg/m² of body surface), for 5consecutive days from day 6 to day 10. A sodium chloride solution of 9g/l is administered twice a day in a proportion of 10ml/kg/administration (approximately 10 hours apart) from day 1 to day 10for group 1, twice a day in a proportion of 5 ml/kg/administration fromday 1 to day 10 for group 2, once a day in a proportion of 20ml/kg/administration from day 1 to day 10 for group 3, and twice a dayin a proportion of 10 ml/kg/administration from day 6 to day 10 forgroup 4. The animals in group 5 receive no 9 g/l sodium chloridesolution.

The mortality and the clinical symptoms are observed every day. The bodyweight is measured on days 3, 6, 10 and 13. The mice are sacrificed andautopsied on day 13. The complete gastrointestinal tract is removed fromall the mice. The gastrointestinal tract of the mice which survived tothe end of the observation period is subjected to examination under amicroscope.

The clinical symptoms observed in all of the groups are similar to thoserecorded in the above study (study I). A reduction in body weight isobserved in all the groups.

The microscopic lesions observed in the intestine correspond to thoseexpected with an anticancer agent. The lesions are mainly in the smallintestine in all the groups. The intestinal lesions are less severe inthe groups which received 9 g/l sodium chloride solution orally than inthe group treated with CPT-11 alone. On the other hand, the incidenceand severity of the intestinal lesions are identical in groups 1 to 4which received, orally, a 9 g/l sodium chloride solution using adifferent administration protocol.

In conclusion, the oral administration of an isotonic sodium chloridesolution (9 g/l) once or twice a day at various administration volumes(5 to 20 ml/kg/administration) before and during, or only during, theintravenous administration of CPT-11 for 5 days prevents in a comparablemanner the occurrence of the intestinal histopathological lesionsinduced by CPT-11.

1.3/Study III

Evaluation of the effect of an orally administered isotonic sodiumchloride solution on the intestinal and systemic toxicity of CPT-11 andon the toxicokinetics of CPT-11 and of its principal metabolite, SN-38.

CD1 male mice (5 to 6 weeks old) are separated into 3 groups of 10. Theanimals of 2 groups receive an intravenous injection (20 ml/kg at a rateof 0.5 ml/minute) of an aqueous solution of CPT-11 in sodium chloride at9 g/l, at the dose of 40 mg/kg (approximately 120 mg/m² of bodysurface), for 5 consecutive days from day 1 to day 5. This period oftreatment is followed by a period of 3 days without treatment (up to day8). In one of these two groups, the mice also receive, orally, anaqueous sodium chloride solution at 9 g/l at a volume of 20 ml/kg/day(i.e. 10 ml/kg/administration, twice a day approximately 10 hours apart)for 5 consecutive days (days 1 to 5) (CPT-11/NaCl group). The animals inthe second group receive no 9 g/l sodium chloride orally (CPT-11 group).In the third group, which did not receive CPT-11, the mice receive,orally, an aqueous sodium chloride solution at 9 g/l at a volume of 20ml/kg/day (i.e. 10 ml/kg/administration, twice a day approximately 10hours apart) for 5 consecutive days (days 1 to 5) (control group). Anadditional 36 animals in the CPT-11 and CPT-11/NaCl groups are used todetermine the plasmatic concentrations of CPT-11 and its principalmetabolite, SN-38.

The mortality and the clinical symptoms are observed every day. The bodyweight is measured on days 1, 3, 6 and 8. The plasma samples for thetoxicokinetic analysis are taken on days 1 and 5. The mice aresacrificed and autopsied on day 8. The relative and absolute weights ofthe thymus, of the spleen and of the testicles are measured, and thecomplete gastrointestinal tract, the sternal bone marrow, the thymus,the spleen, the testicles and the epididymes are removed from all themice and subjected to examination under a microscope.

The maximum plasma concentrations (Cmax) and the areas under the curve(AUC) measured for CPT-11 and SN-38, its principal metabolite, areidentical for the animals in the CPT-11 and CPT-11/NaCl groups on days 1and 5.

The mortality linked to the administration of CPT-11 observed on day 8is observed in 1/10 animals in the CPT-11/NaCl group. The reductions inmotor activity and respiratory difficulties linked to the administrationof CPT-11 are observed occasionally after administration of CPT-11 inthe CPT-11 and CPT-11/NaCl groups, with greater severity in theCPT-11/NaCl group. Identical losses of body weight are observed in theCPT-11 and CPT-11/NaCl groups throughout the treatment with CPT-11, andcontinue after the end of the treatment.

The microscopic lesions observed in the thymus and intestine correspondto those expected with an anticancer agent. The microscopic lesionsobserved in the thymus of the animals in the CPT-11 and CPT-11/NaClgroups are similar and are characterized by lymphoid depletionassociated with a reduction in the weight and size of this organ. Theintestinal microscopic lesions are mainly in the small intestine for theCPT-11 and CPT-11/NaCl groups and are characterized mainly by a loss ofcrypts and atrophy of the villi. The intestinal lesions are less severein the CPT-11/NaCl group than in the CPT-11 group.

In conclusion, the oral administration of an isotonic 9 g/l sodiumchloride solution twice a day at 10 ml/kg/administration (20 ml/kg/day)during the intravenous administration of CPT-11 for 5 days does notmodify the systemic exposure to CPT-11 and to SN-38, does not alter thethymic toxicity of CPT-11, but selectively reduces the severity of theintestinal lesions induced by CPT-11.

1.4/Study IV

Evaluation of the effect of the oral administration of a sodium chloridesolution on the antitumour activity of intravenously administeredCPT-11.

C3H/HeN female mice carrying a mammary adenocarcinoma MA16/C implantedsubcutaneously on day 1 are separated into two groups and receive, ineach of the 2 groups, an intravenous injection (20 ml/kg) of an aqueoussolution of CPT-11 in 5% glucose, at a dose of 14.6, 23.6, 38.0 or 61.3mg/kg, for 5 consecutive days from day 6 to day 10. In one group, themice also received, orally, an aqueous sodium chloride solution at 9 g/lat a volume of 20 ml/kg/day (i.e. 10 ml/kg/administration, twice a dayapproximately 10 hours apart) for 10 consecutive days (days 1 to 10)(group CPT-11/NaCl). The animals in the second group receive no 9 g/lsodium chloride orally (CPT-11 group).

The antitumour activity of CPT-11 is evaluated at the maximum nontoxicdose. A dose which produces a loss of body weight of more than 20%, oran incidence of mortality linked to the administration of CPT-11 of morethan 20%, is considered to be too toxic. The parameters evaluatedinclude the inhibition of tumour growth (T/G) expressed as a percentage,the delay in tumour growth (T-G) and the number of tumour cells killed(Log tumor cell kill=T-G/3.32×tumour doubling time). A Log tumour cellkill value of 0.7 corresponds to minimum activity, while a value greaterthan 2.8 corresponds to a high level of activity.

For the animals in the CPT-11 group, the maximum nontoxic dose of CPT-11is 23.6 mg/kg/day, i.e. a total cumulative dose of 118 mg/kg, themaximum loss of body weight is 10% on day 11 and the Log cell kill valueis 1.7. For the animals of the CPT-11/NaCl group, the maximum nontoxicdose of CPT-11 is 38.0 mg/kg/day, i.e. a total cumulative dose of 190mg/kg, the maximum loss of body weight is 14.1% on day 12 and the Logcell kill value is 2.3.

In conclusion, the oral administration of an isotonic sodium chloridesolution (9 g/l) at 10 ml/kg/administration twice a day (20 ml/kg/day)for 5 days before, and during, the intravenous administration of CPT-11for 5 days does not reduce the antitumour activity of CPT-11.

2/Experimental Study in Dogs

Evaluation of the protective effect of an orally administered sodiumchloride solution on the intestinal toxicity of CPT-11 by theintravenous route.

Six female Beagle dogs (10 to 12 months old) are separated into twogroups of 3 and receive, in each of the 2 groups, a single intravenousinjection (5 ml/kg at a rate of 2 ml/minute) of an aqueous solution ofCPT-11 in sodium chloride at 9 g/l, at a dose of 20 mg/kg (approximately400 mg/M² of body surface), on day 6. In one group, the animals alsoreceive, orally, an aqueous sodium chloride solution. at 9 g/l at avolume of 20 ml/kg/day (i.e. 10 ml/kg/administration, twice a dayapproximately 8 hours apart) for 7 consecutive days (days 1 to 7)(CPT-11/NaCl group) from 5 days before to 1 day after the administrationof CPT-11. The animals in the second group receive no 9 g/l sodiumchloride orally (CPT-11 group). The animals are kept with noadministration for 2 days after the final administration of sodiumchloride at 9 g/l (up to day 9).

The mortality and the clinical symptoms are observed every day. The bodyweight is recorded during the pretest period and on days 5 and 9. Theanimals are sacrificed and autopsied on day 9. Representative tissuesamples taken from the gastrointestinal tract are removed from all theanimals and subjected to examination under a microscope.

The effects linked to the administration of CPT-11 during the period oftreatment comprise salivation, restlessness, vomiting (during orimmediately after the administration of CPT-11), diarrhoea and a slightloss of weight. Observation of the large intestine reveals redness onthe mucosa which is more common in the CPT-11 group than in theCPT-11/NaCl group. The lesions observed result from primary modificationof the proliferative compartment and consist of degeneration of themucosa, and are moderate to pronounced in the CPT-11 group and minimalto mild in the CPT-11/NaCl group.

In conclusion, the intravenous administration of a single dose of CPT-11to female dogs, at the dose of 20 mg/kg, produces gastrointestinaltoxicity compatible with the antimitotic activity of the product. Theoral administration of an isotonic sodium chloride solution (9 g/l) at10 ml/kg/administration twice a day (20 ml/kg/day) from 5 days before to1 day [lacuna] the administration of CPT-11 prevents the occurrence ofthe histopathological lesions induced by CPT-11.

What is claimed is:
 1. A medicinal product comprising: a) a firstsolution comprising one or more camptothecin derivatives, wherein thederivative is of the formula:

 and wherein R₁ is a hydrogen, halogen, or alkyl, X is a chloride atomor NR₂R₃, wherein R₂ and R₃, which may be identical or different, canrepresent a hydrogen atom, an optionally substituted alkyl radical, acarbocycle or a heterocycle which are optionally substituted, or alkylradicals (optionally substituted) forming, with the nitrogen atom towhich they are attached, a heterocycle optionally containing anotherhetero atom chosen from O, S, and/or NR₄, R₄ being a hydrogen atom or analkyl radical, and in which the X—CO—O— group is located in positions 9,10, or 11 on ring A, and b) a second solution consisting essentially ofsodium chloride, which is administered orally during, or before andduring, the administration of the first solution.
 2. The medicinalproduct of claim 1, wherein sodium chloride concentration is between 4and 13 g/l.
 3. The medicinal product of claim 2, wherein the sodiumchloride concentration is 9 g/l.
 4. The medicinal product of claim 1,wherein the camptothecin derivative is irinotecan (CPT-11).
 5. Amedicinal product comprising: a) a first solution comprising one or morecamptothecin derivatives, wherein the derivative is of the formula:

 and wherein R₁ is a hydrogen, halogen, or alkyl, X is a chloride atomor NR₂R₃, wherein R₂ and R₃, which may be identical or different, canrepresent a hydrogen atom, an optionally substituted alkyl radical, acarbocycle or a heterocycle which are optionally substituted, or alkylradicals (optionally substituted) forming, with the nitrogen atom towhich they are attached, a heterocycle optionally containing anotherhetero atom chosen from O, S, and/or NR₄, R₄ being a hydrogen atom or analkyl radical, and in which the X—CO—O— group is located in positions 9,10, or 11 on ring A, and b) sodium chloride which is administered orallyduring, or before and during, the administration of the first solution,further comprising one or more anticancer agents selected from the groupconsisting of cisplatin, oxaliplatin,N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-theonyl-L-glutamicacid)), docetaxel, 5-fluorouracyl and thymidilate synthase inhibitors.6. A method of treating a cancer by administering to a patient aneffective amount of a medicinal product comprising: a) a first solutioncomprising one or more camptothecin derivatives, wherein the derivativeis of the formula:

 and wherein R₁ is a hydrogen, halogen, or alkyl, X is a chloride atomor NR₂R₃, wherein R₂ and R₃, which may be identical or different, canrepresent a hydrogen atom, an optionally substituted alkyl radical, acarbocycle or a heterocycle which are optionally substituted, or alkylradicals (optionally substituted) forming, with the nitrogen atom towhich they are attached, a heterocycle optionally containing anotherhetero atom chosen from O, S, and/or NR₄, R₄ being a hydrogen atom or analkyl radical, and in which the X—CO—O— group is located in positions 9,10, or 11 on ring A; b) a second solution consisting essentially of asodium chloride solution, wherein the second solution is administeredorally during, or before and during, the administration of the firstsolution, and c) wherein the second solution eliminates or reduces thegastrointestinal side effects associated with the administration ofcamptothecin derivatives alone.
 7. The method of claim 6, wherein thecamptothecin derivative is irinotecan (CPT-11).
 8. The method of claim7, wherein the irinotecan is administered in a solution at doses between175 and 500 mg/m² of body surface.
 9. The method of claim 6, wherein thesodium chloride is administered orally in a proportion of 5 to 10ml/kg/administration.
 10. The method of claim 6, wherein the firstsolution of the medicinal product is administered by injection ororally.
 11. The method of claim 6 or 7, wherein the cancer is a cancerof the gastrointestinal tract.
 12. The method of claim 6 or 7, whereinthe cancer is colorectal cancer.
 13. A kit comprising the medicinalproduct of claim 1 or 4, wherein the first and the second solution areintended for separate administration.